1. Field of the Invention
The present invention relates to an AMPK (AMP-activated protein kinase) activating agent.
2. Background of the Invention
In recent years, population with obesity has increased, and so-called lifestyle-related diseases such as diabetes associated with obesity have become grave social problems. Obesity is generated as a result of energy excess in which energy intakes exceed energy consumption. Thus, the bases for prevention and improvement of obesity and diabetes developed therewith are, for example, a decrease in energy intakes by decreasing meal size or an increase in energy consumption by exercise.
However, in the modern society, lipid intakes have increased due to the westernization of eating habits, while the amount of exercise and energy consumption have decreased due to the proliferation of automobiles, and so on. As a result, so-called lifestyle-related diseases such as diabetes have been growing in number with an increase in population with obesity and become grave social problems. Exercise has widely been acknowledged to be effective for preventing and improving a variety of lifestyle-related diseases including obesity and diabetes by promoting energy metabolism. However, it is quite difficult to perform routine exercise in real life. Therefore, it is useful, if possible, to provide some method other than exercise, which has effect similar to that brought by exercise, or to effectively exploit the action of the limited exercise. Namely, the development of exercise-substituting means that exhibits effect similar to that of exercise despite that no actual exercise has been demanded.
For example, many compounds and extracts such as a soybean extract (JP-A-2003-286180), cyanidin 3-glucoside (JP-A-2003-252766), sugarcane polyphenol (JP-A-2003-137803), D-cysteinolic acid (JP-A-2003-104879), and conjugated trienoic acid-based oil and fat (JP-A-2002-186424) have heretofore been founded as substances preventing or improving obesity. However, most of their mechanisms of action on the improvement of obesity remain unknown. Moreover, their safety is not sufficiently confirmed owing to poor history of use in foods. Thus, the fact is that their usefulness is not sufficiently established.
On the other hand, as studies on energy metabolism and on mechanisms of obesity and diabetes onset have proceeded, AMPK has been shown to play a pivotal role therein (Molecular Medicine, Vol. 39, No. 4, p. 398-407, 2002). AMPK (AMP-activated protein kinase) is a ubiquitous protein in living bodies present in the muscles, liver and the like, and is known to be a protein whose activity is elevated under such circumstances that intracellular ATP levels are decreased, thereby promoting metabolism and ATP synthesis (“metabolic sensor”). Namely, AMPK is known to promote energy consumption through its activation. However, recent research has suggested that AMPK is not only regulated by intracellular energy levels but also activated by muscular activity, leptin (Nature, Vol. 415, p. 339-343, 2002), adipocyte-derived hormones such as adiponectin (Nature, Vol. 423, p. 762-769, 2003), metformin, a therapeutic drug for diabetes, (J. Clin. Invest., Vol. 108, p. 1167-1174, 2001), and so on, and acts as an intracellular mediator of fatty acid oxidation or glucose utilization promoting action induced by them. For example, AMPK is known to activate, through the control of acetyl-CoA carboxylase (ACC) activity, carnitine palmitoyltransferase (CPT-1) that transfers long-chain fatty acid to mitochondria, thereby promoting fatty acid oxidation. Namely, CPT-1 is strongly inhibited by malonyl-CoA, an ACC product, while AMPK is considered to phosphorylate Ser79 of the ACC, thereby suppressing the ACC activity. This suggests that drugs that activate AMPK are useful for preventing and treating lifestyle-related diseases including obesity and diabetes by promoting fatty acid oxidation and increasing energy expenditures or are useful for removing lack of exercise by exerting effect similar to that of exercise.
In addition to leptin, adiponectin, and metformin described above, AICAR (5-aminoimidazole-4-carboxamide) has previously been known as a compound that activates AMPK. However, easily available raw materials with rich history of use in foods, high safety, and excellent workability were very few until now.
In recent years, reduced endurance attributed to lack of exercise has been a problem along with the rapid aging of the population, the sophistication of transportation systems, and the progression of information/communication technology. Endurance is essential to not only athletic exercise but also all routine bodily movements including working, walking, and standing. Thus, endurance is exceedingly important for living a meaningful and healthy daily life. Exercise is said to be appropriate for enhancing endurance. However, the fact is that many persons cannot make enough time for exercise due to busyness or can not do exercise due to physical problems even if they want to do so.
Possible one means for solving these problems is to routinely ingest food ingredients having endurance-enhancing or antifatigue action. For example, the present inventors have found endurance-enhancing effect provided by the consumption of catechin (JP-A-2005-89384). Additional examples of the ingredients previously reported to have endurance-enhancing effect include a hawthorn extract (JP-A-08-47381), a Fomes japonicus component (JP-A-05-123135), and proanthocyanidin and lycopene (JP-A-2003-334022). Moreover, examples of the ingredients having antifatigue effect include a composition containing coenzyme Q10 and carnitine (JP-A-2005-97161) and a glutamine peptide (JP-A-2005-97162).
Nootkatone is 4,4a,5,6,7,8-hexahydro-6-isopropenyl-4,4a-dimethyl-2(3H)-naphthalenone or sesquiterpene ketone, is a substance that is present in grapefruit peels and the like, and has received much attention as a flavor because of its characteristic flavor and taste of grapefruit (“Latest Encyclopedia of Perfume and Flavor” edited by Soichi Arai, 1st ed., Asakura Publishing, May 10, 2000, p. 113, p. 254). However, its physiological activity has hardly been reported so far. Regarding grapefruits, a perfume composition containing grapefruit oil (essential oil) has been reported to activate the sympathetic nervous system, thereby exhibiting antiobesity action (JP-A-2002-193824), and an external skin preparation containing grapefruit oil (JP-A-2005-47935) has also been reported. The antiobesity action of nootkatone has never been known. Moreover, the influence of nootkatone on exercise capacity including endurance or on fatigue has never been known so far.